Analysis of human prostate cancers and cell lines for mutations in the TP53 and KLF6 tumour suppressor genes.

A recent report suggests that the KLF6 gene encoding the Krüppel-like factor 6 protein is a frequently mutated, putative tumour suppressor gene in prostate cancer. The aims of the present study were to confirm these initial findings by determining the frequency of exon2 KLF6 mutations in a cohort of European prostate cancer patients, and to investigate whether there was evidence for mutational inactivation of both the KLF6 and TP53 tumour suppressor loci in some tumours. We examined 32 primary prostate tumours and three prostate tumour cell lines for mutations by PCR amplification and direct dideoxy sequencing (KLF6), and by oligonucleotide microarray (p53GeneChip) analysis and dideoxy sequencing (TP53). Whereas TP53 mutations typical of prostate cancer were found at a frequency consistent with the literature, no KLF6 mutations were found in any of the tumour samples nor in the three prostate cancer cell lines.

Pharmaceutical care services for asthma patients: a controlled intervention study.

As asthma is associated with an enormous social, psychological, and economic burden, various patient education programs have been developed to improve outcomes, including quality of life. The authors evaluated the effectiveness of community pharmacy-based interventions on lung function, health-related quality of life, and self-management in asthma patients in a 12-month controlled intervention study in 26 intervention and 22 control pharmacies. Pharmacies opted whether to take part as intervention or control pharmacies. According to this, patients (ages 18-65) with mild to severe asthma attending the pharmacies were allocated to the intervention (n = 161) or control group (n = 81), respectively. Intervention patients were educated on their disease, pharmacotherapy, and self-management; inhalation technique was assessed and, if necessary, corrected. Pharmaceutical care led to significantly improved inhalation technique. Asthma-specific quality of life and the mental health summary score of the SF-36 improved significantly in the intervention group. At 12 months, the intervention group showed significant improvements with regard to evening peak flow, self-efficacy, and knowledge.

p53 gene mutation analysis in tumors of patients exposed to alpha-particles.

The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure. None of the tumors we examined harbored the hotspot mutation. Five of the 50 tumors, however, did indeed harbor exon 7 mutations, as determined by subsequent mutation analysis of exon 7. These mutations were dispersed among various codons and may be attributable to heavy tobacco smoking in this cohort. In support of this interpretation, we found no mutations in exons 5-8 of the p53 gene in 13 iatrogenic liver cancers induced by injection of Thorotrast, an alpha-emitting radiocontrast agent. We propose that if the p53 tumor suppressor gene is a target for the carcinogenic action of alpha-particle radiation, loss of suppressor function may occur preferentially by mechanisms such as intrachromosomal deletions, rather than by base substitution mutations.

[Color duplex sonography of the penis--examination technique and clinical results]. / Farb-Duplexsonographie des Penis--Untersuchungstechnik und klinische Ergebnisse.

40 patients with suspected vasculogenic impotence were examined with color duplex sonography. Penile vascular anatomy was mapped and peak velocity was determined in both cavernosal arteries before and after intracorporeal injection of 15 mg papaverine and 0.5 mg regitine. A peak velocity exceeding 25 cm/sec was considered normal. In 20 patients the results could be compared with internal iliac angiography as the gold standard. In 18 of 20 patients, color duplex sonography and angiography led to identical evaluation of penile blood supply. Two false-negative findings were due to significant lesions of the internal iliac and pudendal artery with extensive collaterals to the penile arteries. One color dulex finding was false positive. Color duplex sonography is a sensitive and non-invasive method for evaluation of arteriogenic impotence. Only angiography, however, can delineate proximal arterial lesions. It remains indispensible if revascularisation is planned.

[Technique and value of digital subtraction angiography in erectile dysfunction]. / Technik und Wertigkeit der DSA bei erektiler Dysfunktion.

Arteriography of penile arterial supply is of decisive importance in the diagnostic evaluation of arteriogenic impotence. Technique and results of penile arteriography by means of high-resolution DSA in 26 impotent men are reported. In comparison to direct serial angiography on large-scale films, high-resolution DSA with 1024(2)-matrix provides the advantages of reduced investigation-time and reduction of contrast media load. Additional detailed views in different projections can be easily obtained. In 15 of 26 patients (mean age 54.9 years) a total of 34 steno-occlusive vessel changes were found (57.7%). 65.4% showed anatomic variations. In all patients, DSA provided clear vascular diagnosis. Thus, additional large-scale serial filming never became necessary. Results are comparable to those reported by other authors. In conclusion, high-resolution DSA can completely replace large-scale serial angiography in the evaluation of penile arterial supply.

Synthesis and characterization of steroid-linked N-(2-chloroethyl)nitrosoureas.

Syntheses of steroid-linked N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-(CNC-) amino acid esters and -amides with potential antineoplastic activity are described. The esters are prepared by reaction of CNC-amino acids with steroids using N,N'-carbonyldiimidazole and N,N'-dicyclohexylcarbodiimide. The corresponding amides are prepared by reaction of 1-(CNC-amino acyloxy)-pyrrolidine-2,5-diones with 17 beta-amino-3-hydroxy-1,3,5(10)-estratriene or 17 beta-O-[4-(6-aminohexylamino)-1,4-dioxo-butyl]-estradiol. Estradiol-17 beta-hemisuccinate is esterified with N-(2-hydroxyethyl)-N'-(2-chloro-ethyl)-N'-nitrosourea (HECNU). Spectroscopic characteristics and relative binding affinities to steroid receptors are given.

Nitrosoureas. Modes of action and perspectives in the use of hormone receptor affinity carrier molecules.

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds are discussed. CNUs are alkylating agents that form DNA-DNA cross-links as well as 2-chloroethylated and 2-hydroxyethylated adducts, the N-7-position of guanine being the predominantly alkylated site. A close correlation exists between the potential of a given compound to induce DNA-DNA cross-links and its antineoplastic effectiveness. However, levels of DNA-DNA cross-linking in bone marrow and extent of myelosuppression as measured in rodents are also closely correlated. The design of new cross-linking analogues capable of directing the antineoplastically relevant activity predominantly to the target tumour appears therefore to be of great promise. Cross-linking agents have been attached to a variety of steroid hormone carrier molecules and the conjugates have been tested in structure-activity studies using hormone-receptor containing animal tumours. These studies have revealed that some hormone-linked antineoplastic agents are highly effective in receptor positive experimental tumours and are superior to mixtures of unlinked alkylating agents with hormones. Indications for a relative enrichment of DNA damaging effects in the tumour tissue and for reduced myelotoxicity have been obtained with specific hormone conjugates.